It is becoming increasing apparent that alterations in myocardial fatty acid metabolism play a key role in a variety of cardiac disorders such as in normal aging, diabetes mellitus, and dilated cardiomyopathy. It has also been shown that estrogen increases myocardial fatty acid metabolism in skeletal muscle in humans whereas progesterone attenuates this effect. Furthermore, premenopausal women have a lower incidence of cardiovascular disease; however, this difference disappears and subsequently reverses following menopause. Lastly, results of studies in experimental animals and our own preliminary studies in post-menopausal women suggest estrogen increases myocardial fatty acid metabolism. Thus, we hypothesize that estrogen increases myocardial fatty acid utilization and oxidation in females. Furthermore, we hypothesize that SERMs that are estrogen receptor agonists will also increase myocardial fatty acid metabolism. To prove or disprove these hypotheses, we will aim to determine: 1.) in healthy post-menopausal women, whether estrogen will increase myocardial fatty acid utilization and oxidation and whether progesterone will attenuate this effect 2.) in ovariectomized mice, the extent to which candidate SERMs Raloxifene and Tamoxifen increase myocardial fatty acid metabolism and whether the increase in comparable to that observed with estrogen and 3.) in estrogen receptor knockout mice, the role of the estrogen receptor isoforms alpha and beta in the modulation of myocardial fatty acid metabolism by estrogen and the SERM identified in Aim 2. Measurements of myocardial fatty acid metabolism will be performed with PET and micro-PET imaging using well-validated radiotracer kinetic methods. The study is designed to first prove that estrogen modulates myocardial substrate metabolism in post-menopausal women. Then it will be determined if the SERMs Tamoxifen and Raloxifene are estrogen-like in their effects on myocardial metabolism in mice. Finally, the mechanism responsible for the estrogen and SERM effects on myocardial fatty acid metabolism will be assessed in estrogen knockout mice. In addition to answering these questions, the proposed project would allow Dr. Pablo Soto to more fully develop as an independent investigator in translational research involving non-invasive imaging under the guidance of Dr. Robert Gropler, a leading expert in PET assessment of myocardial metabolism.